Usage and dosage of therapeutic agents for endometriosis

ABSTRACT

An object of the present invention is to provide pharmaceutical agents that reduce risk for decrease in bone mineral density due to their effect of reducing estrogen levels and exert excellent therapeutic effects on endometriosis. The present invention relates to pharmaceutical compositions for treating endometriosis comprising 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, which are administered orally once a day at a daily dose of between 50 mg and 75 mg calculated as a free form.

TECHNICAL FIELD

The present invention relates to pharmaceutical agents that reduce riskfor decrease in bone mineral density due to their effect of reducingestrogen levels and exert their excellent therapeutic effects onendometriosis.

More specifically, the present invention relates to pharmaceuticalcompositions for treating endometriosis comprising3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid or a pharmaceutically acceptable salt thereof, which areadministered orally once a day at a daily dose of between 50 mg and 75mg calculated as a free form.

BACKGROUND ART

Endometriosis is a disease in which endometrium or similar tissue growsat sites outside the uterus depending on the increased estrogen level.Although endometriosis is a benign disease, it causes pain such asmenstrual pain and reduces fertility, and significantly reduces thequality of life (QOL) of women in their social and reproductiveactivities. Women with endometriosis have menstrual pain at an extremelyhigh frequency and a symptom of pain such as lower abdominal pain not attheir menstruation, low back pain, pain during or after sexualintercourse, pain during defecation and so on at a high frequency.

Many patients repeat exacerbation or recurrence of endometriosis beforethe menopause and thus endometriosis requires long-term treatment andmanagement, unless they receive a radical surgical operation. As thefirst treatment for endometriosis, medication therapy is often selected.Medication therapy is generally classified into symptomatic andendocrine therapies. For symptomatic therapy, a medicine such as ananalgesic agent is used in order to reduce endometriosis-associatedpain. For endocrine therapy, in addition to reduction of pain, alow-dose formulated estrogen-progestin agent, dienogest, or gonadotropinreleasing hormone (GnRH) agonist is used in order to suppressestrogen-dependent growth of endometrium.

Analgesic agents, however, have been considered not to be able to reduceendometriosis-associated pain in 10% to 30% of patients withendometriosis. Furthermore, in using a low-dose formulatedestrogen-progestin agent, care should be taken for thrombosis, liverdysfunction and the others. Dienogest has been reported in a long-termstudy to have a 71.9% incidence of atypical genital bleeding as a sideeffect, which may result in severe anemia. GnRH agonists are, basically,not allowed to be administered for more than 6 months for a possibledecrease of bone mineral density due to a decline in estrogen levels.

As described above, in medication therapy for treating endometriosis,continuous administration of medicament is difficult in many patientsdue to side effects specific for each of pharmaceutical agents.Accordingly, development of pharmaceutical agents that have fewer sideeffects and can be administered for a long period has been desired.

In the treatment of endometriosis, a concept called “estradioltherapeutic window” has been proposed as a threshold for blood estradiol(E2) level under which serious decrease of bone mineral density due tothe effect of reducing estrogen levels does not occur while suppressinggrowth of the lesions of endometriosis (NPL 1). For example, NPL 1describes that a therapeutic window would be an E2 level between 30pg/mL and 50 pg/mL. Furthermore, it suggests that, at estradiolconcentrations of lower than 20 pg/ml, the legions of endometriosisshould atrophy but decrease of bone mineral density should be prominent.

3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid (hereinafter, referred to as Compound 1) represented by thefollowing formula (I) is described in PTL 1. A choline salt of Compound1 (hereinafter, referred to as Compound 2) is described in PTL 2. PTL 1and PTL 2 describe that the Compound 2 and fused heterocyclicderivatives containing Compound 1 antagonize GnRH and can be used aspharmaceutical agents for preventing or treating sex hormone-dependentdiseases such as prostatic hypertrophy, uterine fibrosis, endometriosis,uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome,and dysmenorrhea. PTL 1 and PTL 2 also describe that an oral dosage formcan be manufactured in such a manner that the fused heterocyclicderivative or Compound 2 is administered at a dose ranging between 0.1mg and 1000 mg.

PTL 1 and PTL 2 only describe general medical applications and generaldosage of Compound 2 and fused heterocyclic derivatives containingCompound 1 based on GnRH antagonist activity. They do not specificallydescribe usages and dosages of Compounds 1 and 2 with which risk fordecrease in bone mineral density due to their effect of reducingestrogen levels is reduced and their excellent therapeutic effects areexerted on endometriosis.

CITATION LIST Patent Literature

-   PTL 1: International Publication WO2007/046392-   PTL 2: International Publication WO2011/099507

Non Patent Literature

-   NPL 1: Robert L. Barbieri, “The Journal of Reproductive Medicine,”    1998, 43, supplement, 287-292

SUMMARY OF INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide pharmaceutical agentsthat reduce risk for decrease in bone mineral density due to theireffect of reducing estrogen levels and exert excellent therapeuticeffects on endometriosis.

Means for Solving the Problems

The present inventors found, as a result of extensive studies to achievethe aforementioned object, an optimum balance of efficacy and sideeffects as well as usages and dosages of Compound 1 with which risk fordecrease in bone mineral density due to its effect of reducing estrogenlevels is reduced.

The present invention relates to the following [1] to [5].

[1] A pharmaceutical composition for treating endometriosis comprising3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid or a pharmaceutically acceptable salt thereof, the compound beingadministered orally once a day at a daily dose of between 50 mg and 75mg calculated as a free form.[2] The pharmaceutical composition according to [1], wherein thepharmaceutically acceptable salt is3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid choline salt.[3] The pharmaceutical composition according to [1] or [2], wherein thedaily dose is 50 mg calculated as a free form.[4] The pharmaceutical composition according to [1] or [2], wherein thedaily dose is 75 mg calculated as a free form.[5] The pharmaceutical composition according to any one of [1] to [4],wherein the composition for treating endometriosis is a composition fortreating endometriosis-associated pain.

As one embodiment, the present invention relates to a method of treatingendometriosis comprising administering a necessary amount of apharmaceutical composition containing3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid or a pharmaceutically acceptable salt thereof to a patient, whereinthe compound is administered orally once a day at a daily dose ofbetween 50 mg and 75 mg calculated as a free form.

As one embodiment, the present invention relates to use of3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid or a pharmaceutically acceptable salt thereof for manufacturing apharmaceutical composition for treating endometriosis, wherein thecompound is administered orally once a day at a daily dose of between 50mg and 75 mg calculated as a free form.

Advantageous Effects of Invention

The pharmaceutical compositions of the present invention reduce risk fordecrease in bone mineral density due to their effects of decline inestrogen levels and exert their excellent therapeutic effects onendometriosis.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows NRS scores of patients with endometriosis. The verticalaxis represents changes in average NRS for pelvic pain (regardless ofwhether subjects were at their menstruation or not) from thepre-treatment period (Changes in average NRS of pelvic pain). Thehorizontal axis represents time of measurements. “Pre treatment”represents the pre-treatment period, “Week 4,” “Week 8,” and “Week 12”represent 4 weeks, 8 weeks, and 12 weeks, respectively, after thebeginning of administration, and “End of Treatment” represents the timeof final assessment during the treatment period. In the figure, blacksquares represent values for a group administered with 50 mg, blacktriangles represent values for a group administered with 100 mg, blackcircles represent values for a group administered with 200 mg, and whitesquares represent values for a placebo group.

FIG. 2 shows E2 concentrations in patients with endometriosis during thetreatment period. The vertical axis represents mean values of E2concentrations (pg/m L). The horizontal axis represents time ofmeasurements. “Pre treatment” represents the pre-treatment period, and“Week 4,” “Week 8,” and “Week 12” represent 4 weeks, 8 weeks, and 12weeks, respectively, after the beginning of administration. In thefigure, black squares represent values for a group administered with 50mg, black triangles represent values for a group administered with 100mg, black circles represent values for a group administered with 200 mg,and white squares represent values for a placebo group.

MODE FOR CARRYING OUT THE INVENTION

Embodiments of the present invention are described more in detail below.

In the present invention, words and terms have the following meaning,unless specified otherwise.

In the present invention, Compound 1 means“3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid” and Compound 2 means“3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid choline salt.” The Compound 1 and“5-carboxy-3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione”described in PTL 1 are the same compound.

In the present invention, Compound 1 can be converted to apharmaceutically acceptable salt thereof according to a general method,if necessary. Examples of such salts include sodium salts, potassiumsalts, and organic base salts such as N,N′-dibenzyl entylenediamine,2-aminoethanol, and choline. A choline salt of Compound 1 (i.e.,Compound 2) is preferable.

In the present invention, the term “pharmaceutically acceptable salt ofCompound 1” also includes a solvate thereof with a pharmaceuticallyacceptable solvent such as water and ethanol.

Compounds 1 and 2 of the present invention can be produced using a knownmethod. For example, Compounds 1 and 2 of the present invention can bemanufactured using a method described in WO 2007/046392 (PTL 1) and WO2011/099507 (PTL 2), respectively, or other similar method.

The pharmaceutical compositions of the present invention can take anyone of various dosage forms depending on their usage. Examples of suchdosage forms include oral formulations such as powders, granules, finegranules, dry syrups, tablets, and capsules.

The pharmaceutical compositions of the present invention are preparedusing Compound 1 or a pharmaceutically acceptable salt thereof as anactive ingredient, and at least one pharmaceutical additive. Thepharmaceutical compositions of the present invention can also beprepared by being appropriately mixed with, diluted with or dissolved ina pharmaceutical additive using a pharmaceutically known methoddepending on their dosage form. Examples of such pharmaceuticaladditives include excipients such as lactose, lubricants such asmagnesium stearate, disintegrating agents such as carboxymethylcellulose, binders such as hydroxypropyl methylcellulose, surfactantssuch as macrogols, foaming agents such as sodium hydrogen carbonate,solubilizing agents such as cyclodextrin, acidifiers such as citricacid, stabilizers such as disodium edetate, and pH adjusting agents suchas phosphates.

The pharmaceutical compositions of the present invention are useful astherapeutic agents for endometriosis and have one or more of effects ofreducing pain (e.g., pelvic pain, pain during defecation, pain duringvaginal examination, and pain during or after sexual intercourse)associated with endometriosis, effects of reducing the size of ovarianchocolate cysts associated with endometriosis, effects of improvingobjective findings (e.g., induration of Douglas' pouch and limiteduterine mobility), and reduction in use rate for analgesic agents.

As one embodiment, since menstruation cycles are maintained duringtreatment of endometriosis depending on their embodiment, thepharmaceutical compositions of the present invention can be used forpatients with endometrium who don't want to interrupt menstruation.

In the present invention, a daily dose of an active ingredient (Compound1 or a pharmaceutically acceptable salt thereof) to adult patients canbe determined within a range of between 50 mg and 75 mg for oraladministration (if Compound 1 is in the form of a pharmaceuticallyacceptable salt thereof, it can be determined within a range of between50 mg and 75 mg calculated as a free form). For example, for adultpatients, an initial dosage can be 50 mg or 75 mg calculated as a freeform of Compound 2, and Compound 2 can be administered orally at 50 mgor 75 mg calculated as a free from during treatment. The amount ofCompound 2 used can appropriately be increased or decreased within arange between 25 mg and 100 mg calculated as a free form at thediscretion of the physician depending on the age and body weight of thepatient, extent of disease and/or level of side effects observed.

The pharmaceutical compositions of the present invention can beadministered, for example, starting from the first to fifth days ofmenstruation.

Exemplified usage and dosage of the pharmaceutical compositions of thepresent invention can be as follows: Compound 2 is administered orallyonce a day at a daily dose of 50 mg or 75 mg calculated as a free form.

The daily dose can be increased or decreased within the aforementionedrange at the discretion of the physician. The daily dose can be dividedinto two or three doses.

In the present invention, the phrase “risk for decrease in bone mineraldensity due to the effect of reducing estrogen levels” means risk fordecrease in bone mineral density associated with suppression of E2secretion. The degree of the “risk for decreased bone mineral densitydue to a decline in estrogen levels” by the pharmaceutical compositionsof the present invention can be evaluated based on the E2 concentrationor the development of symptoms of hypoestrogenism such as hot flashes,headache, dizziness and hyperhidrosis.

With the pharmaceutical compositions of the present invention, E2 can beadjusted to an appropriate concentration at which risk for decrease inbone mineral density due to the effect of reducing estrogen levels canbe reduced. An appropriate E2 concentration is preferably between 20pg/mL and 50 pg/mL, more preferably, between 30 pg/mL and 50 pg/mLduring treatment.

The pharmaceutical compositions of the present invention can reduce sideeffects resulting from excessive suppression of E2 secretion, forexample, the development of symptoms of hypoestrogenism such as hotflashes, headache, dizziness and hyperhidrosis associated with theadministration of a pharmaceutical agent.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Examples. However, the present invention is not limitedthereto. In the Examples, the dosage (dose) of Compound 2 means a dosagecalculated as a free form (value calculated as a free from) unlessotherwise specified.

Example 1

Clinical Trial 1 in Patients with Endometriosis (Double-BlindParallel-Group Comparison Study)

1. Methods

To 107 patients with endometriosis, Compound 2 at a dose of 50 mg (29patients), 100 mg (26 patients) or 200 mg (28 patients) or a placebo (24patients) was orally administered after breakfast once a day for 12weeks. These groups are hereinafter referred to as a 50-mgadministration group, a 100-mg administration group, a 200-mgadministration group, and a placebo group. The administration wasstarted from the second to fifth days of menstruation.

2. Evaluation Scales for Effectiveness and Safety

As evaluation scales for effectiveness, evaluated were, for example, NRSscores for pelvic pain at menstruation or at other time (from 0: no painto 10: the strongest pain that the subject had experienced before),severity of pelvic pain at menstruation or at other time (from 0: nopain to 4: intolerable even after the use of an analgesic agent),temporary pain (pain during defecation, pain during vaginal examination,and pain during or after sexual intercourse), severity of observationsby others (induration of Douglas' pouch and limited uterine mobility),use rate of an analgesic agent, sizes of an ovarian chocolate cyst andthe uterus, endocrinological examinations (E2, luteinizing hormone (LH),follicle-stimulating hormone (FSH), and progesterone), and the presenceor absence of menstruation.

As evaluation scales for safety, for example, the occurrence of anadverse event, the occurrence of a side effect, and vaginal bleedingwere evaluated.

3. Results

Changes of average NRS scores for pelvic pain (regardless of whether thesubjects were at their menstruation or not) is shown in FIG. 1. Changesin average NRS for pelvic pain (regardless of whether the subjects wereat their menstruation or not) between the pre-treatment period and thetime of the final assessment during treatment were −1.13, −1.27, −1.33,and −0.19 for the 50-mg administration group, the 100-mg administrationgroup, the 200-mg administration group, and the placebo group,respectively. Significant improvements were observed in all groups towhich Compound 2 had been administered as compared to the placebo group.Temporal pain, observations by others, a use rate of an analgesic agent,sizes of an ovarian chocolate cyst and the uterus were also improved inthe groups to which Compound 2 had been administered as compared to theplacebo group.

The numbers of cases where side effects associated with hypoestrogenism(e.g., hot flashes, headache, dizziness and hyperhidrosis) weredeveloped were 9, 12, 28, and 1 for the 50-mg administration group, the100-mg administration group, the 200-mg administration group, and theplacebo group, respectively.

Changes of median E2 concentrations during treatment are shown in FIG.2. Suppression of E2 secretion was observed in all groups to whichCompound 2 had been administered. Analyses of the occurrences of sideeffects associated with hypoestrogenism (e.g., hot flashes, headache,dizziness and hyperhidrosis) for each E2 concentration during treatmentrevealed that the occurrence of side effects was 28.2% in the groupswith E2 concentration of 20 pg/mL and/or more whereas the occurrence ofside effects was 54.8% in the groups with E2 concentration of less than20 pg/mL.

Table 1 shows whether menstruation occurred during treatment. In thetable, “Compound 2 50 mg” means the 50-mg administration group,“Compound 2 100 mg” means the 100-mg administration group, “Compound 2200 mg” means the 200-mg administration group, “Placebo” means theplacebo group, “Yes” represents a percentage of patients who hadmenstruation during treatment, and “No” represents a percentage ofpatients who had no menstruation during treatment. When it wasadministered at a smaller dose, a higher percentage of patients hadmenstruation during treatment.

TABLE 1 Yes No Compound 2 50 mg 72.4% 27.6% Compound 2 100 mg 26.9%73.1% Compound 2 200 mg 3.6% 96.4% Placebo 100.0% 0.0%

Results of Example 1 showed that, in the 50-mg administration group, atherapeutic effect on endometriosis-associated pain was similar to thosein the 100-mg and 200-mg administration groups, and risk for decrease inbone mineral density due to the effect of reducing estrogen levels canbe reduced.

On the other hand, in the 100-mg and 200-mg administration groups,sufficient therapeutic effects on endometriosis-associated pain wereshown but side effects of symptoms of hypoestrogenism appeared at ahigher frequency, and E2 concentrations during treatment were lower than20 pg/mL.

It was also shown that side effects of symptoms of hypoestrogenism werereduced in the groups with E2 concentration of 20 pg/mL and/or moreduring treatment as compared to the groups with E2 concentration of lessthan 20 pg/mL.

Example 2

Clinical Trial 2 in Patients with Endometriosis (Randomized Non BlindParallel-Group Comparison Study)

1. Methods

To 21 patients with endometriosis, Compound 2 was administered orally ata dose of 75 mg (11 patients) or 150 mg (10 patients) after breakfastonce a day for 8 weeks. These groups are hereinafter referred to as a75-mg administration group and a 150-mg administration group. Theadministration was started from the second to fifth days ofmenstruation.

2. Evaluation Scales for Effectiveness and Safety

Scales similar to those in the Example 1 were evaluated as evaluationscales for effectiveness and safety.

3. Results

Changes in average NRS for pelvic pain (regardless of whether thesubjects were at their menstruation or not) between the pre-treatmentperiod and the time of final assessment during the treatment period were−0.94 and −1.68 for the 75-mg administration group and the 150-mgadministration group, respectively. A tendency of improvement wasobserved in all groups to which Compound 2 had been administered.

Median E2 concentrations during treatment were 35 pg/mL and 10 pg/mL onweek 4 and 24 pg/mL and 10 pg/mL on week 8 for the 75-mg and 150-mgadministration groups, respectively.

Results of the Example 2 showed that, in the 75-mg administration groupalso, a therapeutic effect was exhibited close to those obtained in the100-mg and 200-mg administration groups on endometriosis-associatedpain, and risk for decrease in bone mineral density due to the effect ofreducing estrogen levels can be reduced.

Example 3

Clinical Trial 3 in Patients with Endometriosis (Randomized Double-BlindParallel-Group Comparison Study)

1. Methods

To a recruiting goal of 400 patients with endometriosis, Compound 2 isorally administered at a dose of 25 mg, 50 mg, 75 mg or 100 mg or aplacebo after breakfast once a day for 12 weeks. The administration isstarted from the first to fifth days of menstruation.

2. Evaluation Scales for Effectiveness and Safety

As evaluation scales for effectiveness, evaluated are, for example, NRSscores for pelvic pain at menstruation or at other time (from 0: no painto 10: strongest pain that the subject have had before), severity ofpelvic pain at menstruation or at other time (from 0: no pain to 4:intolerable even after the use of an analgesic agent), temporary pain(pain during defecation, pain during vaginal examination, and painduring or after sexual intercourse), severity of observations by others(induration of Douglas' pouch and limited uterine mobility), sizes of anovarian chocolate cyst and the uterus, QOL (Endometriosis HealthProfile-30 (EHP-30)), a use rate of an analgesic agent, endocrinologicalexaminations (E2, luteinizing hormone (LH), follicle-stimulating hormone(FSH), and progesterone), and the presence or absence of menstruation.

As evaluation scales for safety, evaluated are, for example, theoccurrence of an adverse event, the occurrence of a side effect, vaginalbleeding, bone metabolism markers (serum cross-linked N-telopeptide oftype I collagen (serum NTX) and bone alkaline phosphatase (BAP)) andbone density (using the DXA method).

Results of the Examples 1 and 2 indicated that oral administration ofCompound 2 at a daily dose of between 50 mg and 75 mg calculated as afree form once a day resulted in reduced risk for decrease in bonemineral density due to the effect of reducing estrogen levels andexerted excellent therapeutic effects on endometriosis.

INDUSTRIAL APPLICABILITY

The pharmaceutical compositions of the present invention are extremelyuseful as therapeutic agents for endometriosis.

The invention claimed is:
 1. A pharmaceutical composition for treatingendometriosis or an endometriosis-associated pain in a patient, thepharmaceutical composition comprising a compound represented by3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid, or a pharmaceutically acceptable salt thereof, wherein thepharmaceutical composition is orally administrable, and wherein thepharmaceutical composition comprises the compound in an amount of from50 mg to 75 mg calculated as a free form, the amount beingtherapeutically effective for treating the endometriosis or theendometriosis-associated pain in the patient.
 2. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceuticallyacceptable salt is3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid choline salt.
 3. The pharmaceutical composition according to claim1, wherein the pharmaceutical composition comprises 50 mg of thecompound calculated as a free form.
 4. The pharmaceutical compositionaccording to claim 1, wherein the pharmaceutical composition comprises75 mg of the compound calculated as a free form.
 5. A method fortreating endometriosis or an endometriosis-associated pain, the methodcomprising: administering orally once daily the pharmaceuticalcomposition according to claim 1 to a patient.
 6. A method for treatingendometriosis, the method comprising: administering a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundrepresented by3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid, or a pharmaceutically acceptable salt thereof to a patient, thecompound being administered orally once a day at a daily dose of from 50mg to 75 mg calculated as a free form.
 7. The method according to claim6, wherein the pharmaceutically acceptable salt is3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid choline salt.
 8. The method according to claim 6, wherein the dailydose is 50 mg calculated as a free form.
 9. The method according toclaim 6, wherein the daily dose is 75 mg calculated as a free form. 10.A method for treating endometriosis-associated pain, the methodcomprising: administering a therapeutically effective amount of apharmaceutical composition comprising a compound represented by3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid, or a pharmaceutically acceptable salt thereof to a patient, thecompound being administered orally once a day at a daily dose of from 50mg to 75 mg calculated as a free form.
 11. The method according to claim10, wherein the pharmaceutically acceptable salt is3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylicacid choline salt.
 12. The method according to claim 10, wherein thedaily dose is 50 mg calculated as a free form.
 13. The method accordingto claim 10, wherein the daily dose is 75 mg calculated as a free form.